The overall goal of this proposal is to dissect the genetic determinants of individual variation in response to medications used routinely for the treatment and prevention of cardiovascular disease (CVD). We propose two projects, both part of significant ongoing pharmacogenomics studies at the University of Maryland. Both projects will be performed by an established multidisciplinary group that has a track record of publication and productivity, collegial interactions with outside groups, including other NIH funded multi-center networks, and a history of data sharing. Project 1: Pharmacogenomics of anti-platelet agents for CVD prevention: This project seeks to identify specific gene variants that predict response to clopidogrel (Plavix) for the 1[unreadable] and 2[unreadable] prevention of CV events. We will build upon our large ongoing HAPI Heart Study in which 1,000 related Old Order Amish subjects, all of whom have been extensively characterized with respect to CVD (including response to aspirin) and in whom an 800 short tandem repeat marker genome scan has been completed. We propose to treat these same subjects with clopidogrel and to obtain measures of platelet aggregation and function. We will (1) determine the frequency and heritability of clopidogrel response and the relationship between clopidogrel resistance and aspirin resistance;(2) exhaustively define sequence variation and haplotype structure of 100 candidate genes and perform linkage and association analysis of SNPs/haplotypes with platelet function phenotypes;and (3) perform genome-wide linkage analysis to identify chromosome regions (and ultimately genes) linked to clopidogrel response. Project 2: Pharmacogenomics of insulin sensitizing thiazolidinediones (TZDs) for CVD risk reduction: Insulin resistance is thought to play a causative role in the metabolic syndrome, a constellation of CVD risk factors that include central obesity, glucose intolerance, hypertension, and hyperlipidemia. TZDs (e.g., rosiglitazone) are ligands for PPARy, and activate a cascade of genes involved in adipogenesis and insulin signaling. These agents are used routinely to treat insulin resistance and there is substantial evidence that they have beneficial effects on a number of CVD risk factors. As an extension of our ongoing Pharmacogenomics of PPARy project, 75 subjects will undergo extensive phenotypic characterization with respect to insulin sensitivity,inflammatory markers and other measures of CVD risk before and 3 months after being treated with rosiglitazone. Gene expression profiles will be obtained by microarray analysis of both adipose tissue and muscle. We will (1) identify the set of genes (and the corresponding pathways) that are differentially regulated in TZD responders compared to non-responders to define the molecular phenotype of TZD response;(2) exhaustively define sequence variation and haplotype structure of 100 candidate genes;and (3) define sequence variants that influence TZD response through association analysis of SNPs/haplotypes in our population and in other populations (Diabetes Prevention Program, TRIPOD, ARIC). The proposed studies will provide important insights into clopidogrel and TZD response, will have important implications for the prevention and treatment of CVD in millions of Americans.